1. Field of the Invention
The present invention relates to benzamidine derivatives, and pharmacologically acceptable salts and prodrugs thereof, which have excellent activated blood coagulation factor X inhibitory activity. The present invention also concerns a pharmaceutical composition for the prevention or treatment of blood coagulation-related diseases, comprising said benzamidine derivative, or a pharmacologically acceptable salt or prodrug thereof. The present invention is further directed to the use of said benzamidine derivative, or a pharmacologically acceptable salt or prodrug thereof for the preparation of a medicament for the prevention or treatment of blood coagulation-related diseases. The present invention also relates to a method for the prevention or treatment of blood coagulation-related diseases comprising administering to a warm blooded animal in need of such prevention or treatment a pharmacologically effective amount of said benzamidine derivative, or a pharmacologically acceptable salt or prodrug thereof. The present invention also involves processes for the preparation of said benzamidine derivatives, and pharmacologically acceptable salts and prodrugs thereof.
2. Background Information
Recently the proportion of the population of an advanced age is increasing and the increase of patients with circulatory disease accompanying aging is remarkable. Of the diseases, thromboses such as cerebral embolus, myocardial infarction, peripheral circulatory disease and the like not only directly become the cause of a person's death, but also lead to a private and social burden, which comprise unsatisfactory recuperation of the patient and a restricted private life of the patient. It is considered that anti-coagulation treatment will be increasingly important as a thrombosis treatment.
Blood coagulation is caused by formation of fibrin. Fibrin is formed by the selective decomposition of fibrinogen, which is a soluble serum protein, by activated thrombin, which is produced at the end of an amplified multi-step enzyme reaction activated by some stimulus. Fibrin is an insoluble protein and causes coagulation. This process is known as a blood coagulation cascade and comprises an internally caused process and an externally caused process. Both processes come together at the activation of blood coagulation factor X. The activated blood coagulation factor X thus formed is an important enzyme in the blood coagulation cascade. The activated blood coagulation factor X ultimately forms a complex with divalent calcium ions, phosphatide, activated blood coagulation factor V and the like, effectively converting pro-thrombin to thrombin and enhancing the blood coagulation reaction (for example, see E. L. Smith, A. White et al., “Principles of Biochemistry: Mammalian Biochemistry 7th edition”, McGraw-Hill, Inc. (1983)).
At the present time, warfarin and anti-thrombin agents are known as anti-blood coagulation agents. Warfarin has widely been used as an oral anti-thrombus agent. However it is known that the control of blood coagulation activity with warfarin is difficult, because it is a vitamin K antagonist and often has an interaction with a meal and with agents combined with warfarin (for example, Clin. Pharmacokinet., 30, 416 (1996) and the like). Recently bleeding has been obserbed as an adverse effect of anti-thrombin agents. Therefore an improved anti-blood coagulation agent has been expected. It has been known that the activated blood coagulation factor X is directly involved in the formation of thrombin and that inhibitors of activated blood coagulation factor X exhibit anti-blood coagulation activity. The possibility that such an inhibitor might become a new anti-blood coagulation agent has been suggested (for example, Drugs, 49, 856 (1995) and the like).
Incidentally some aromatic amidine derivatives and amidinonaphthyl derivatives are disclosed in Japanese patent application publication number Hei 5-208946 (EP 540051), WO 96/16940 (EP 798295) and WO 00/47553 as competitive-antagonistic activated blood coagulation factor X inhibitors. Some benzamidine derivatives, for example N-[4-[1-acetimidoyl-4-piperidyloxy]phenyl]-N-[2-(3-amidinophenoxy)ethyl]sulfamoylacetic acid ditrifluoroacetate are described in WO 98/31661 (EP 976722).